Vascular endothelial cells participate in acute and inflammatory reactions. A marked feature of this reaction is a selective early influx of neutrophils from the peripheral blood. Circulating and bone marrow neutrophils provide a front line of defense that is rapidly mobilized and activated against infectious agents.
When foreign invaders such as bacteria, viruses or other invading parasites penetrate the skin or mucous membranes, an inflammatory response is mounted. This is characterized by dilation of surrounding blood vessels, an increase in vascular permeability, and the migration of monocytes and neutrophils across vascular walls. The first step in extravasation involves adhesive interactions of leukocytes with the vascular endothelium, which must be regulated to allow localization of leukocytes only at inflammatory sites.
Recent studies have demonstrated that certain inflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and gram-negative bacterial endotoxin (lipopolysaccharide) can act directly on vascular endothelium in vitro to increase the adhesiveness of the endothelial blood cells for blood leukocytes as well as related leukocyte cell lines (HL-60 and U937). Studies of human and animal tissues indicate that a similar process of endothelial activation occurs in various inflammatory disease processes in vivo.
After attachment to endothelial cells or other cells, neutrophils may exert damaging effects through several mechanisms. Upon stimulation, neutrophils generate and release toxic oxygen metabolites, numerous proteases, and phospholipase products, all of which may result in vasomotor changes, endothelial injury and loss of vascular integrity. Increased neutrophil adhesiveness is a critical, early step in the sequence of events leading to neutrophil-mediated injury. Increased adhesiveness results in neutrophil adhesion to endothelium or other cells and/or neutrophil aggregation.
Therefore, the inhibition of leukocyte adhesion potentially is of central importance in therapeutic interventions in inflammatory disease processes. While leukocyte adhesion is normally desirable, it is also implicated in immune and .nonimmune disease processes, including organ transplant rejection, tissue graft rejection, allergic reactions, autoimmune diseases, rheumatoid arthritis, septic shock, adult respiratory distress syndrome (ARDS), glomerulonephritis, and other tissue or organ-specific forms of acute and chronic inflammation. Further, in the setting of ischemia-reperfusion, leukocyte adhesion may produce microvascular occlusion, tissue injury and death.
The present invention is drawn to compositions which are potent modulators of neutrophil functions. These compositions have important anti-inflammatory properties which support their use as protective agents in neutrophil-mediated endothelial and other tissue injury.